TGF-beta superfamily signaling has long been strongly implicated in pancreatic endocrine cell development and specifically pancreatic beta cell formation. Because of the size and complexity of the superfamily it has been difficult to garner a clear understanding of signaling mechanisms. The smad family of transcription factors is a relatively small family that serves as the downstream mediator of TGF-beta superfamily signaling. Because of its relative simplicity, we have chosen to focus on smad signaling in order to begin to unravel the key mechanisms by which TGF-beta superfamily molecules regulate pancreatic islet cell formation, especially beta cells. We have preliminary evidence that TGF-beta superfamily signaling, through smads 2 and 3, control recruitment of endocrine progenitor cells from the multipotent pancreatic epithelium in the embryonic mouse. After this initial recruitment of endocrine progenitor cells, these smads seem to then regulate pancreatic endocrine maturation and proliferation. The function of these two smads appears to be critically modulated by one of the inhibitory smads, smad7. Importantly, we have also shown a potential parallel role for smads 2 and 3, and the inhibitory smad7, in the regeneration of new beta cells in the adult mouse pancreas in response to a partial pancreatectomy. It appears that most new beta cells form from previous beta cells, but little or nothing is know about endogenous extracellular signals that regulate this new formation of beta cells. Thus, this proposal will focus on smad signaling in the embryo and in the regenerating islet in order to better understand the extracellular signaling through TGF-beta superfamily that leads to the formation of new beta cells. The study of extracellular signaling mechanisms that lead to new pancreatic beta cell formation are important since engineering of cells for the treatment of diabetes mellitus ought to involve only extracellular manipulations rather than intracellular (genetic) manipulations. We have identified a key parallel between embryonic islet cell formation and adult islet regeneration that may give us insights into the mechanisms by which extracellular signaling may be used to engineer beta cells. PUBLIC HEALTH RELEVANCE: The study of extracellular signaling mechanisms that lead to new pancreatic beta cell formation are important since engineering of cells for the treatment of diabetes mellitus ought to involve only extracellular manipulations rather than intracellular (genetic) manipulations. We have identified a key parallel between embryonic islet cell formation and adult islet regeneration that may give us insights into the mechanisms by which extracellular signaling may be used to engineer beta cells.